ABSTRACT Major depressive disorder (MDD) is prevalent and debilitating, and development of improved treatments is limited in part by insufficient understanding of the mechanism of disease remission. In turn, efforts to elucidate mechanisms have been challenging due to disease heterogeneity and limited effectiveness of treatments, which require weeks-to-months to induce remission. In this application, we propose to focus on applying a novel neurostimulation strategy to participants with TRD. We recently developed a form of repetitive transcranial magnetic stimulation that induces remission in 90% of individuals with severe, treatment resistant MDD in 1-5 days which we called Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT). This methodology provides a new tool to begin exploring the network-level mechanisms of MDD remission. Following SAINT, fc significantly decreases default mode network (DMN)-subgenual cingulate cortex (sgACC) which is correlated with change in clinical scales. In this application, we propose to target the L-DLPFC-sgACC target with active (n=50) versus sham (n=50) SAINT and determine if active SAINT (Aim 1) attenuates sgACC-DMN connectivity and (Aim 2) significantly reduces symptoms of depression. Decreases in fc may underlie reductions in depression; thus, we will relate reductions in these potential moderators to identify the best symptom targets. Completion of this proposal will further establish a safe, effective, and non-invasive device-based treatment for TRD along with the iterative neural circuitry changes at each daily dose of stimulation that summate to produce the clinical effect.